The cornified cell envelope constitutes a multi-component 15 nm thick layer of highly insoluble protein on the inside of the plasma membrane of terminally differentiated epithelial cells. Based on a variety of data, we now know that loricrin is a major component of the epidermal cell envelope. It is crosslinked to the envelope by way of N~-(~- glutamyl)lysine isodipeptide crosslinks, catalyzed by the action of transglutaminases. Loricrins are glycine-rich proteins that contain the highly flexible glycine loop motif. We have expressed human locricrin in a baculovirus system to study its biochemical properties and the mechanism(s) by which it is crosslinked. In order to study its precise role in the epidermis, and the regulation of its expression, we have used transgenic technology. A construct containing the full-length human gene and flanking sequences can direct the proper site- and stage-specific over-expression of human loricrin in transgenic mice. Since the mice are normal, loricrin is presumably a very late, if not the last, component to be added to the cell envelope.